Principles of Drug Metabolism, with an Emphasis on Psychiatric Drugs

  • Ronald T. Coutts
  • jian Fang
  • Michel Bourin
  • Glen B. Baker
Part of the Neuromethods book series (NM, volume 33)


A knowledge of how drugs are metabolized in the body is often of clinical relevance because often an administered drug is not soley responsible for observed pharmacological and toxicological effects. Regrettably, the formation of drug metabolites is often not considered in pharmacological evaluations, the assumption being that it is the drug itself that is the active species. In many instances, desirable and undesirable drug effects can be correlated with rates of biotransformations and the properties of metabolites; pharmacokinetic drug-drug interactions may also occur if a patient is receiving two or more drugs that compete for the same metabolic enzymes. In the present chapter, we will concentrate on metabolism of drugs used to treat psychiatric disorders, although the principles and protocols discussed are applicable to other classes of drugs as well.


  1. Agúndez, J A., Jiménéz-Jimenez, F. J, Luengo, A., Bernal, M L, Molina, J A., Ayuso, L, Vazquez, A, Parra, J, Duarte, J., Cona, F, Ladero, J M, Alvarez, J. C. and Benitez, J (1995b) Association between the oxidative polymorphism and early onset of Parkinson’s disease. Chn. Pharmacol Ther. 57, 291–269.Google Scholar
  2. Agundez, J A, Ledesma, M. C, Ladero, J M., and Benitez, J. (1995a) Preva lence of CYP2D6 gene duplication and its repercussion on the oxidative phe notype in a white population Clin Pharmacol Ther 57, 265–269PubMedGoogle Scholar
  3. Ameer, B and Weintraub, R A (1997) Drug interactions with grapefruit juice Clin Pharmacokinet 33, 103–121PubMedGoogle Scholar
  4. Arana, G W, Goff, D C, Friedman, H., Ornsteen, M., Greenblatt, D J, Black, B and Shader R.I (1985) Does carbamazepme-induced reduction of plasma ha loperidol levels worsen psychotic symptoms? Am J Psychiatry 143, 650–651Google Scholar
  5. Anens’ E. J., Wuis, E. W., and Vennga, E. J. (1988) Stereoselectivity of bioactive xenobiotics Biochem Pharmacol 37, 13–18.Google Scholar
  6. Baker, G B, Coutts, R T, and Holt, A. (1994) Metabolism and chirality in psy chopharmacology Biol Psychiatry 36, 211–213PubMedGoogle Scholar
  7. Baker, G B, Urichuk, L J, and Coutts, R T (1998) Drug metabolism and meta bolic drug-drug interactions in psychiatry. Child and Adolescent Psycho pharmacol News (suppl)., in press.Google Scholar
  8. Balant-Gorgm, E. A and Balant, L P (l995)Therapeutic drug monitoring relevance during the drug treatment of psychiatric disorders CNS Drugs 4, 243–253Google Scholar
  9. Baldessarini, P A and Cole J O (1995) Interactions of serotonin reuptake inhibi tors with tricyclic antidepressants-in reply. Arch Gen Psychiat 52, 784,785Google Scholar
  10. Baumann, P (1996a) Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors Clin Pharmacokinet 31, 444–469PubMedGoogle Scholar
  11. Baumann, P (1992) Clinical pharmacokinetics of citalopram and other selective serotonin reuptake inhibitors (SSRI) Int Clin Psychopharmacol 6, 13–20PubMedGoogle Scholar
  12. Baumann, P. (1996b) Pharmacology and pharmacokinetics of citalopram and other SSRls Int Clin Psychopharmacol ll(Suppl.), 5–11Google Scholar
  13. Baumann, P and Rochat, B (1995) Comparative pharmacokinetics of selective serotonin reuptake inhibitors a look behind the mirror Int Clin Psycho pharmacol 10(Suppl.), 15–21Google Scholar
  14. Benet, L Z, Kroetz, D L., and Sheiner, L B (1996) Pharmacokinetics the dynamics of drug absorption, distribution and elimination, in Goodman & Gilman’s The Pharmacological Basis of Therapeutics (Hardman, J G, Limbird, L E, Molinoff, P. B and Ruddon, R W, eds), McGraw-Hill, New YorkGoogle Scholar
  15. Bergstrom, R F, Peyton, A L, and Lemberger, L (1992) Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction Clin Pharmacol Ther 51, 239–248PubMedGoogle Scholar
  16. Bertilsson, L, Carrillo, J A, Dahl, M L, Llerena, A, Aim, C, Bondesson, U, Lindstrom, L, Rodriguez de la Rubia, I, Ramos, S, and Benitez, J (1994) Clozapine disposition covaries with CYP1A2 activity determined by a caf feine test Br J Clin Pharmacol 38, 471–473PubMedGoogle Scholar
  17. Bertilsson, L, Henthorn, T K, Sanz, E, Tybring, G, Sawe, J, and Villen, T (1989) Importance of genetic factors in the regulation of diazepam meta bolism Relationship to S-mephenytoin, but not debrisoquin, hydroxylation phenotype Clin Pharmacol Ther 45, 348–355PubMedGoogle Scholar
  18. Bertz, R J and Granneman, G R. (1997) Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions Clin Pharmacokinet 32, 210–258PubMedGoogle Scholar
  19. Blake, B L, Rose, R. L, Mailman, R. B, Levi, P. E, and Hodgson, E (1995) Metabolism of thioridazine by microsomal monooxygenases relative roles of P450 and flavin-containing monooxygenase. Xenobiotica 25, 377–393PubMedGoogle Scholar
  20. Bolaji, O O, Coutts, R T, and Baker, G B (1993) Metabolism of tnmipramine in vitro by human CYP2D6 isozyme Res Commun Chem Path Pharmacol 82, 111–120Google Scholar
  21. Boulton, A A, Baker, G B., and Coutts, R T., eds (1988) Analysis of psychiat ric drugs Neuromethods, vol. 10, Humana Press, Totowa, New JerseyGoogle Scholar
  22. Bourne, M, Meunier, V, Berger, Y, and Fabre, G (1996) Cytochrome P450 isoform inhibitors as a tool for the investigation of metabolic reactions cata lyzed by human liver microsomes. J Pharmacol Exp Ther 277, 321–332Google Scholar
  23. Brenner, D D and Schellens, J H M. (1990) A’ cocktail’ strategy to assess in vivo oxidative drug metabolism in humans Trends Pharmacol Sci 11, 223–225Google Scholar
  24. Britto, M R and Wedlund, P J (1992) Cytochrome P-450 in the brain Potential evolutionary and therapeutic relevance of localization of drug-metabolizing enzymes Drug Metab Dispos 20, 446–450PubMedGoogle Scholar
  25. Brosen, K (1993a) Isozyme specific drug oxidation: genetic polymorphism and drug-drug interactions. Nord J Psychiat. 47(Suppl. 30), 21–26.Google Scholar
  26. Brosen, K (1993b) The pharmacogenetics of the selective serotonin reuptake inhibitors. Clin Invest. 71, 1002–1009Google Scholar
  27. Brosen, K and Skjelbo, E (1991) Fluoxetine and norfluoxetine are potent inhibitors of P450IID6-the source of the sparteine/debrisoquine oxidation polymorphism. Br J Clin Pharmacol 32, 137,138Google Scholar
  28. Caldwell, J (1992) The importance of stereochemistry in drug action and disposition J Clin Pharmacol. 32, 925–929PubMedGoogle Scholar
  29. Caldwell, J (1996) Importance of stereospecific bioanalytical monitoring in drug development J Chromatogr 719, 3–13Google Scholar
  30. Camilleri, P, de Baisi, V,, and Hutt, A (1994) Resolving the problem Chemistry in Britain, 30, 43–46Google Scholar
  31. Carson, S. W (1996) Pharmacokinetic and pharmacodynamic drug interactions with polypharmacotherapy of treatment-resistant affective and obsessive compulsive disorders. Psychopharmacol. Bull 32, 555–568Google Scholar
  32. Cholerton, S., Daley, A K, and Idle, J R (1992) The role of individual human cytochromes P450 in drug metabolism and clinical response Trends Pharmacol Sci 13, 434–439PubMedGoogle Scholar
  33. Ciraulo, D A, Shader, R 1, Greenblatt, D J., and Creelman, W. L, eds (1995) Drug Interactions in Psychiatry, Williams & Wilkins, Baltimore, MDGoogle Scholar
  34. Ciraulo, D. A. and Shader R. 1 (1990a) Fluoxetine drug-drug interactions I Antidepressants and antipsychotics J Clin Psychopharmacol 10, 48–50PubMedGoogle Scholar
  35. Ciraulo, D A, and Shader R. 1. (1990b) Fluoxetine drug-drug interactions II J Clin. Psychopharmacol. 10, 213–217PubMedGoogle Scholar
  36. Coutts, R. T (1994) Polymorphism in the metabolism of drugs, including antidepressant drugs comments on phenotyping J Psychiat Neurosci 19, 30–44Google Scholar
  37. Coutts, R T., Bach, M. V., and Baker, G B (1997) Metabolism of amitriptyline with CYP2D6 expressed in a human cell line Xenobiotica 27, 33–47PubMedGoogle Scholar
  38. Coutts, R T, Su, P., Baker, G B, and Daneshtalab, M (1993) Metabolism of lmipramine in vitro by CYP2D6 expressed in a human cell line, and observa tions on metabolite stability J Chromatogr Biomed Appl 6115, 265–272Google Scholar
  39. Coutts, R T and Baker, G B (1989) Implications of chirahty and geometric isomerism in some psychoactive drugs and their metabolites Chirahty 99–120Google Scholar
  40. Daniel, W (1995) Metabolism of psychotropic drugs’ pharmacological and clini cal relevance Pol J Pharmacol Pharm 47, 367–379Google Scholar
  41. Degtyarenko, K N and Fabian, P (1996) The directory of P450-contaming sys tems on WorldWide Web Computer Appl. Bwsctences 12, 237–240.Google Scholar
  42. DeVane, C L (1994) Pharmacogenetics and drug metabolism of newer anti depressant agents J Clin Psychiat 55(Suppl.), 38–45Google Scholar
  43. Drayer, D E (1988) Problems in therapeutic drug monitoring the dilemma of enantiomeric drugs in man Ther Drug Monit 10, 1–7PubMedGoogle Scholar
  44. Ducharme, J, Fernandez, C, Gimenez, F., and Fannotti, R. (1996) Critical issues in chiral drug analysis in biological fluids by high-performance liquid chro matography J Chromatog B Biomed Appl 686, 65–75Google Scholar
  45. Eap, C. B, Bertschy, G, Powell, K, and Bauman, P (1997) Fluvoxamine and fluoxetine do not interact in the same way with the metabolism of the enan tiomers of methadone J. Clin Psychopharmacol 17, 113–117PubMedGoogle Scholar
  46. Eap, C B and Baumann, P (1996) Analytical methods for the quantitative determination of selective serotonin reuptake inhibitors for therapeutic drug monitoring purposes in patients J. Chromatogr 686, 51–63Google Scholar
  47. Edge, S C, Markowitz, J S, and DeVane, L. (1997) Clozapine drug-drug inter actions. a review of the literature Human Psychopharmacol 12, 5–20Google Scholar
  48. Eichelbaum, M (1992) Pharmacokinetic and pharmacodynamic consequences of stereoselective drug metabolism in man. Bwchem Pharmacol 37, 93–96Google Scholar
  49. Eiermann, B M, Engel, G., Johansson, I, Zanger, U M, and Bertilsson, L (1997) The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine Br J Clin. Pharmacol 44, 439–446.PubMedGoogle Scholar
  50. Ereshefsky, L., Riesenman, C, and Lam, Y M F (1995) Antidepressant drug interactions and the cytochrome P450 system the role of cytocyrome P450 2D6 Clin Pharmacokinet 29, 10–19PubMedGoogle Scholar
  51. Fang, J, Coutts, R T, McKenna, K F, and Baker, G B (1998) Elucidation of individual cytochrome P450 enzymes involved m the metabolism of clozapine Naunyn Schmiedeberg’s Arch Pharmacol (in press).Google Scholar
  52. Fang, J, Baker, G B., Silverstone, P H, and Coutts, R T (1997) Involvement of CYP3A4 and CYP2D6 in the metabolism of halopendol Cell Mol Neurobiol 17, 227–233.PubMedGoogle Scholar
  53. Fang J, Baker G. B, Coutts R T., and McKenna K F (1996) Elucidation of indi vidual cytochrome P450 isoenzymes involved in the metabolism of clozapine Proc 7th North American ISSX Meeting, San Diego, California, USA, October 20-24, 1996.Google Scholar
  54. Gaedigk, A, Blum, M, Gaedigk, R., Eichelbaum, M, and Meyer, U A. (1991) Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabohzers of the debrisoqume/sparteine poly morphism Am J Hum Genet 48, 943–950PubMedGoogle Scholar
  55. Garfinkel, D (1958) Studies on pig liver microsomes 1 Enzymatic and pig ment composition of different microsomal fractions Arch Biochem Bio physics 77, 493–509Google Scholar
  56. Gibaldi, M (1993) Stereoselective and isozyme-selective drug interactions Chirality 5, 407–413PubMedGoogle Scholar
  57. Gibson, G G and Skett, P (1988) Introduction to Drug Metabolism, Chapman and Hall, LondonGoogle Scholar
  58. Glue, P. and Clement, R P (1998) Cytochrome P-450 enzymes and drug metabolism-basic concepts and methods of assessment Cell Mol Neurobwl (in press)Google Scholar
  59. Glue, P and Banfield, C (1996) Psychiatry, psychopharmacology and P-450s Hum Psychopharmacol. 11, 97–114Google Scholar
  60. Goldstein, J. A, Faletto, M. B., Romkes-Sparks, M., Sullivan, T, Kitareewan, S, Raucy, J L, Laskar, J. M and Ghanayem, B. 1 (1994) Evidence that CYP2C19 is the major (S)mephenytoin 4’-hydroxylase in humans Biochemistry 33, 1743–1752PubMedGoogle Scholar
  61. Gonzales, F J. and Korzedwa, K R (1995) Cytochrome P450 expression systems Ann Rev Pharmacol Toxicol 35, 369–390Google Scholar
  62. Gorog, S and Gazdag, M. (1994) Enantiomeric derivatization for biomedical chromatography J Chromatogr 659, 51–84Google Scholar
  63. Greenblatt, D J., von Moltke, L L, Schmider, J., Harmatz, J S, and Shader, R. I. (1996) Inhibition of human cytochrome P450-3A isoforms by fluoxetine and norfluoxetine in vitro and in vivo studies J Clin Pharmacol 36, 792–798.PubMedGoogle Scholar
  64. Guengerich, F. P (1995) Human cytochrome P-450 enzymes, in Cytochrome P-450, 2nd Ed. (Ortiz de Montellano, P. R, ed.), Plenum Press, New YorkGoogle Scholar
  65. Hamehn, B A., Turgeon, J., Vallee, F., Belanger, P M., Paquet, F, and LeBel, M. (1996) The disposition of fluoxetine but not sertraline is altered in poor metabohzers of debrisoquin. Clin Pharmacol. Ther 60, 512–521Google Scholar
  66. Hansson, T, Tindberg, N, Ingelman-Sundberg, M, and Kohler, C (1990) Regional distribution of ethanol-inducible cytochrome P450 IIEl in the rat CNS. Neuroscience 34, 451–463PubMedGoogle Scholar
  67. Harvey, A. T and Preskorn, S. H. (1996a) Cytochrome P450 enzymes interpre tation of their interactions with selective seroltonin reuptake inhibitors Part I J Clin. Psychopharmacol 16, 273–285.PubMedGoogle Scholar
  68. Harvey, A. T and Preskorn, S H. (1995) Interactions of serotonin reuptake inhibitors with tricyclic antidepressants. Arch. Gen Psvchtat 52, 783,784Google Scholar
  69. Harvey, A. T. and Preskorn, S. H. (1996b) Cytochrome P450 enzymes interpre tation of their interactions with selective seroltonin reuptake inhibitors, Part II. J Clin Psychopharmacol 16, 345–354PubMedGoogle Scholar
  70. Hedlund, E, Wyss, A, Kainu, T, Backlund, M, Kohler, C, Pelto-huikko, M., Gustafsson, J-A and Warner, M (1996) Cytochrome P4502D4 in the brain specific neuronal regulation by clozapine and toluene. Mol Pharmacol 50, 342–350.PubMedGoogle Scholar
  71. Heim, M. H. and Meyer, U. A (1991) Genetic polymorphism of debrisoquine oxidation4 restriction fragment analysis and allele-specific amplification of mutant alleles of CYP2D6 Meth Enzymol 206, 173–183PubMedGoogle Scholar
  72. Henthorn, T. K., Benitez, J, Avram, M. J., Martinez, C, Lierena, A, Cobaleda, J., Krejcie, T C, and Gibbons, R. D (1989) Assessment of the debrisoquin and dextromethorphan phenotyping tests by gaussian mixture distributions analysis. Clin Pharmacol Ther 45, 328–333.PubMedGoogle Scholar
  73. Houston, J B. (1994) Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem Pharmacol, 47, 1469–1479PubMedGoogle Scholar
  74. Huang, M-L., Van Peer, A., Woestenborghs, R, DeCoster, R, Heykants, J, Jansen, A. A. I, Zylicz, Z Visscher, H W, and Jonkman, J H G (1996) Pharmacokinetics of the novel antipsychotic agent risperidone and the pro lactin response in healthy subjects Clin Pharmacol Ther 54, 257–268.Google Scholar
  75. Hubbard, J. W., Ganes, D, Lim, H. K., and Midha, K K (1986) Chiral pharmacol ogy and its consequences for therapeutic monitoring Clin Btochem 19, 107–112.Google Scholar
  76. Hutt, A. J and Tan, S C (1996) Drug chirality and its clinical significance Drugs 52, 1–12PubMedGoogle Scholar
  77. Hutt, A. J, Hadley, M. R., and Tan, S. C (1994) Enantiospecific analysis Applica tions in bioanalysis and metabolism. Eur J Drug, Metab Pharmacokin 19, 241–251.Google Scholar
  78. Jamah, F, Mahvar, R., and Pasutto, F, M (1989) Enantioselective aspects of drug action and disposition, therapeutic pitfalls. J Pharm Sci 78, 695–715Google Scholar
  79. Jeppesen, U., Gram, L. F., Vistisen, K., Loft, S, Poulsen, H E, and Brosen, K, (1996) Dose-dependent inhibition of CYP1A2, CYP2C19, CYP2D6 by citalopram, fluoxetine, fluvoxamine, and paroxetine Eur J Clin Pharmacol 51, 73–78PubMedGoogle Scholar
  80. Jerling, M, Dahl, M-L, Aberg-Wistedt, A, et al (1996) The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol Chn Pharmacol Ther 59, 423–428Google Scholar
  81. Kalow, W. and Tyndale, R. F. (1992) Debrisoquine/sparteine monooxygenase and other P-450s in the brain, in Pharmacogenetics of Drug Metabolism. International Encyclopedia of Pharmacology and Therapeutics (Kalow, W, ed), Pergamon Press, New York, pp 649–656Google Scholar
  82. Kempermann, G, Knoth, R., Gebicke-Haerter, P J, Stolz, B J, and Yolk, B (1994) Cytochrome P450 in rat astrocytes in vivo and in vitro intracellular localization and induction by phenytoin J. Neurosci Res 39, 576–588PubMedGoogle Scholar
  83. Kobayashi, K, Yamamoto, T., Chiba, K., Tani, M, Ishizak, T, and Kurolwa, Y (1995)The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4’-hydroxylase activity in human liver microsomes Br J Clin Pharmacol 40, 481–485PubMedGoogle Scholar
  84. Kroemer, H K and Eichelbaum, M (1995) It’s the genes, stupid Molecular bases and clinical consequences of genetic cytochrome P450 2D6 polymor phism. Life Sci 56, 2285–2298PubMedGoogle Scholar
  85. Kronbach, T, Mathys, D, Umeno, M, Gonzalez, F J, and Meyer, U A (1989) Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4 Mol Pharmacol 36, 89–96PubMedGoogle Scholar
  86. Kopfer, A and Preisig, R (1984) Pharmacogenetics of mephenytoin a new drug hydroxylation polymorphism in man Eur J Clm Pharmacol 26, 753–759Google Scholar
  87. Lam, Y W F, Jann, M W, Chang, W-H, Yu, H-S, Lin, S-K., Chen, H., and Davis, C. M. (1995) Intra-and interethnic variability m reduced halopendol to halopendol ratios J Clin Pharmacol 35, 128–136PubMedGoogle Scholar
  88. Lane, R M. (1996) Pharmacokinetic drug interaction potential of selective sero tonin reuptake inhibitors. Int Clin Psychopharmacol 11, 31–61PubMedGoogle Scholar
  89. Lane, R M and Baker, G B (1998) Chirality and drugs used in psychiatry nice to know, or need to know? Cell Mol Neurobiol (in press)Google Scholar
  90. Liccione, J J and Maines, M D (1989) Manganese-mediated increase in the rat brain mitochondrial cytochrome-P-450 and drug metabolism activity-sus ceptibility of the striatum J Pharmacol Exp Ther 248, 222–228PubMedGoogle Scholar
  91. Lin, K.-M, Poland, R E, Wan, Y-J Y, Smith, W, and Lesser, I M (1996) The evolving of pharmacogenetics clinical and ethnic perspectives Psychopharmacol Bull 32, 205–217PubMedGoogle Scholar
  92. Marzo, A (1994) Incoming guidelines on chirality-A challenge for pharmaco kinetics in drug development Arzneimittelforschung 44-1, 6Google Scholar
  93. Messiha, F S (1993) Fluoxetine, adverse effects and drug-drug interactions Clin Toxicol 31, 603–630Google Scholar
  94. Meyer, U A, Amnen, R, Balant, L P, Bertilsson, L, Eichelbaum, M, Geuntert, T. W, Henauer, S, Jackson, P, Laux, G, Mikkelson, H, Peck, C, Pollock, B G, Proest, R, Sjoqvist, F, and Denhni-Stula, A (1996) Antidepressants and drug-metabolizing enzymes-expert group report Acta Psychiat Scand 93, 71–79PubMedGoogle Scholar
  95. Midha, K K, Hawes, E M, Hubbard, J W, Korchinski, E D, and McKay G (1987) The search for correlations between neuroleptic plasma levels and clinical outcome a critical review, in Psychopharmacology The Third Genera tion of Progress (Meltzer, H Y, ed), Raven Press, New YorkGoogle Scholar
  96. Miners, J O and Birkett, D J (1998) Cytochrome P4502C9-an enzyme of major importance in human drug metabolism Br J Clin Pharmacol 45, 525–538PubMedGoogle Scholar
  97. Muralidharan, G, Hawes, E M, McKay, G, Korchmski, E D, and Midha, K K (1991) Qumidine but not quinine inhibits in man the oxidative metabolic routes of methoxyphenamine which involve debrisoquine 4-hydroxylase Eur J Pharmacol 41, 471–474Google Scholar
  98. Mutschler, E, Gietl, Y, Krauss, D, Martin, E., Pflugmann, G, and Weber, H (1990) Stereospecif ic analysis and human pharmacokinetics of the enantiomers of drugs administered as racemates, in Chirality and Biological Activity (Holmstedt, B, Frank, H, and Testa, B, eds), Alan R Liss, New York, pp.199–219Google Scholar
  99. Nebert, D W, Nelson, D R, Adesnik, M, Coon M J, Estabrook, R W, Gonzalez, F J, Guengerich, F P, Gunsalus, I C, Johnson, E. F, Kemper, B, Levin, W, Philips, I R, Sato, R and Waterman, M R (1989) The P450 super-family. updated listing of all genes and recommended nomenclature for the chromosomal loci DNA 8, 1–13PubMedGoogle Scholar
  100. Nelson, D R, Kamataki, T, Waxman, D. J, Guengerich, F L, Estabrook, R W, Feyereisen, R, Gonzalez, F J, Coon, M J, Gunsalus, I C, Gotoh, O, Okuda, K, and Nebert, D W (1993) The P450 superfamily update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature DNA Cell Biol 12, 1–51PubMedGoogle Scholar
  101. Nelson, D R, Koymans, L, Kamataki, T., Stegeman, J J, Feyereisen, R, Waxman, D J, Waterman, M R, Gotoh, O, Coon, M J, Estabrook, R W, Gunsalus, I C, and Nebert, D W (1996) P450 superfamily update on new sequences, gene mapping, accession numbers and nomenclature Pharmacogenetics 6, 1–42.PubMedGoogle Scholar
  102. Nemeroff, C B, DeVane, C L, and Pollock, B G (1996) Newer antidepres sants and the cytochrome P450 system Am J Psychiat 153, 311–320PubMedGoogle Scholar
  103. Olkkola, K T, Aranko, K, Luunla, H, Hiller, A, Saaemvaara, L, Himberg, J J, and Neuvonen, P J (1993) A potentially hazardous interaction between erythromycin and midazolam. Clin Pharmacol Ther 53, 298–305PubMedGoogle Scholar
  104. Omura, T and Sato, R (1962) A new cytochrome in liver microsomes J Biol Chem 237, PC1375–PC1376Google Scholar
  105. Ortiz de Montellano, P R, ed (1996) Cytochrome P450, in, Structure, Mecha nism, and Biochemistry, 2nd ed, Plenum Press, New YorkGoogle Scholar
  106. Parkinson, A (1996) Biotransformation of xenobiotics, in Casarett and Doull’s Toxicology The Basic Science of Poisons, 5th edition (Klaasen, C D, ed), McGraw-Hill, New York, NY, pp 113–186.Google Scholar
  107. Perault, M C, Bouquet, S, Bertschy, G, Vandel, S, Chakroun, R, Guibert, S, and Vandel, B (1991) Debnsoqume and dextromethorphan phenotyping and antidepressant treatment. Therapie 46, 1–3.PubMedGoogle Scholar
  108. Pirmohamed, M, Williams, D., Madden, S, Templeton, E, and Park, B K (1995) Metabolism and bioactivation of clozapine by human live in vitro J Pharmacol Exp Ther 272, 984–990PubMedGoogle Scholar
  109. Poph, A, Baldessarim, R. J, and Cole, J O. (1995) Interactions of serotonin reuptake inhibitors with tricyclic antidepressants-in reply. Arch Gen Psy chiatry, 52, 784,785Google Scholar
  110. Potter, W Z and Manji, H K. (1990) Antidepressants, metabolites, and appar ent drug resistance Clin Neuropharmacol 13(Suppl. 1), S45–S53PubMedGoogle Scholar
  111. Preskorn, S H (1996) Clinical Pharmacology of Selective Serotonin Reuptke Inhibi tors, 1st ed, Professional Communications Inc, Caddo, OKGoogle Scholar
  112. Preskorn, S H (1997) Clinically relevant pharmacology of selective serotonin reuptake inhibitors an overview with emphasis on pharmacokinetics and ef fects on oxidative drug metabolism Clin Pharmacokinet 32,(Suppl. 1), 1–21PubMedGoogle Scholar
  113. Raitasuo, V, Lehtovaara, R, and Huttunen, M O (1993) Carbamazepine and plasma levels of clozapine. Am J Psychiatry 150, 169PubMedGoogle Scholar
  114. Richelson, E (1997) Pharmacokinetic drug interactions of new antidepressants A review of the effects on the metabolism of other drugs Mayo Clin Proc 72, 835–847.PubMedGoogle Scholar
  115. Ring, B J, Catlow, J, Lindsay T, Gillespie, T, Roskos, K, Cenmele, B J, Swanson, S P, Hamman, M. A, and Wrighton, S A (1996) Identification of the human cytochromes P450 responsible for the invitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine J Pharmacol Exp Ther 276, 658–666PubMedGoogle Scholar
  116. Rodngues, A D (1994) Use of in vitro human metabolism studies in drug development. Biochem Pharmacol. 48, 2147–2156.Google Scholar
  117. Rosholm, N F. and Brosen, K (1995) Lack of relationship between quinidine pharmacokinetics and the sparteine oxidation polymorphism Eur J Clin Pharmacol 48, 501–504PubMedGoogle Scholar
  118. Rudorfer, M V and Potter, W Z (1985) Metabolism of drugs used in affective disorders, in Pharmacotherapy of Affective Disorders, Theory and Practice (Dewhurst, W G and Baker, G B, eds.), N Y University Press, New York, pp 382–448Google Scholar
  119. Schmid, B, Bircher, J, Preisig, R and Kupfer, A (1989) Polymorphic dextromethorphan metabolism. Cosegregation of oxidative O-demethylation with debnsoquine hydroxylation Clin Pharmacol Ther 38, 618–624Google Scholar
  120. Schmider, J., Greenblatt, D J., von Moltke, L L., Karsov, D, and Shader, R I (1997) Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in vitro studies of phenytoin p-hydroxylation J Clin Pharmacol 44, 495–498Google Scholar
  121. Schung, V (1994) Enantiomer separation by gas chromatography on chiral sta tionary phases J Chromatog 666, 111–129Google Scholar
  122. Segel, I H (1975) Enzyme Kinetics Behavior and Analysis of Rapid Equilibrium and Steady-State Enzyme Systems, John Wiley and Sons, New York, NYGoogle Scholar
  123. Sequeira, D J and Strobel, H W. (1996) In vitro metabolism of imipramine by brain micosomes effects of inhibitors and exogenous cytochrome P450 reductase. Brain Res 738, 24–31.PubMedGoogle Scholar
  124. Shen, W. W (1997) The metabolism of psychoactive drugs A review of enzy matic biotransformation and inhibition Biol Psychiatry 41, 814–826PubMedGoogle Scholar
  125. Shimada, T, Yamazaki, H., Mimura, M, Inui, Y, and Guengench, F P (1994) Intenndividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals Studies with liver microsomes of 30 Japanese and 30 Caucasians J Pharmacol Exper Ther 270, 414–423Google Scholar
  126. Smith, D. F (1984) CRC Handbook of Stereoisomers Drugs in Psychopharmacology, CRC Press Inc., Boca Raton, FLGoogle Scholar
  127. Spina, A, Avenoso, A, Campo, G, Caputi, A. P, and Perucca, E (1995) The ef fect of carbamazepine on the 2-hydroxylation of desipramine Psychopharmacol 117, 413–416.Google Scholar
  128. Spina, E and Perucca, E (1994) New and older antidepressants a comparative review of drug interactions CNS Drugs 2, 479–497Google Scholar
  129. Sproule, B. A, Naranjo, C A., Bremmer, K. E, and Hassan, P C (1997) Selec tive serotonin reuptake inhibitors and CNS drug interactions Clin Pharmacokinet 33, 454–471PubMedGoogle Scholar
  130. Srinivas, N R, Shyu, W C, and Barbhalya, R, H (1995) Gas chromatographic determination of enantiomers as diastereomers following pre-column derivatization and applications to pharmacokinetic studies, a review Biomed Chromatog 9, 1–9Google Scholar
  131. Su, P., Coutts, R T, Baker, G. B., and Daneshtalab, M. (1993) Analysis of uni pramine and three metabolites produced by isozyme CYP2D6 expressed in a human cell line Xenobiotica 23, 1289–1298PubMedGoogle Scholar
  132. Subert, J (1994) Progress in the separation of enantiomers of chiral drugs by HPLC without their prior derivatization. Pharmazie 49, 3–13.Google Scholar
  133. Syrek, M., Wojcikowski, J, and Daniel, W. (1996) Effect of carbamazepine on the pharmacokinetics of promazine. Pol.J Pharmacol 48, 601–608PubMedGoogle Scholar
  134. Taylor, D. (1995) Selective serotonin reuptake inhibitors and tricyclic antide pressants in combination Interactions and therapeutic uses. Br J Psychiatry 167, 575–580PubMedGoogle Scholar
  135. Taylor, D. and Lader, M (1996) Cytochromes and psychotropic drug interactions Br. J Psychiat 168, 529–533.Google Scholar
  136. Teboul, E. and Chouinard, G. (1991) A guide to benzodiazepine selection, part II, clinical aspects. Can J Psychiat. 36, 62–73Google Scholar
  137. Terabe, S., Otsuka, K., and Nishi, H (1994) Separation of enantiomers by capil lary electrophoretic techniques J Chromatogr. A. 666, 295–319Google Scholar
  138. Testa, B (1986) Chiral aspects of drug metabolism Trends Pharmacol Set 7, 60–64Google Scholar
  139. Van Harten, J (1993) Clinical pharmacokinetics of selective serotonin reuptake inhibitors Clin Pharmacokinet 24, 203–220PubMedGoogle Scholar
  140. Vespalec, R and Bocek, P (1994) Chiral state of the art. Electrophoresis 15, 755–762PubMedGoogle Scholar
  141. von Bahr, C, Movin G, Nordin, C, Linden, A, Hammarlund-Udenases, M., Hedberg, A, Ring, H., and Sjoquist, F. (1991) Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype Clin Pharmacol Ther 49, 234–240.Google Scholar
  142. von Moltke, L L, Greenblatt, D J, Harmatz, J. S., and Shader, R. 1 (1993) Alprazolam metabolism m vitro studies of man, monkey, mouse and rat liver microsomes Pharmacology 47, 268–276.Google Scholar
  143. von Moltke, L. L., Greenblatt, D J., Harmatz, J. S, Duan, S. X., and Harrel, L. M. (1996) Triazolam biotransformation by human liver microsomes in vitro effects of metabolic inhibitors and clinical confirmation of a predicted inter action with ketoconazole. J Pharmacol Exp Ther 276, 370–379Google Scholar
  144. von Moltke, L L, Greenblatt, D. J, Duan, S. X, Schmider, J, Kudchadker, L, Fogelman, S. M, Harmatz, J S., and Shader, R 1. (1996) Phenacetm O-dee thylation by human liver microsomes in vitro, inhibition by chemical probes, SSRI antidepressants, nefazodone, and venlafaxine. Psychopharmacology 128, 398–407.Google Scholar
  145. von Moltke, L L, Greenblatt, D J, Cotreau-Bibbo, M., Duan, S X., Harmatz, J. S., and Shader, R. 1. (1994) Inhibition of desipramine hydroxylation in vitro by serotonin-reuptake inhibitor antidepressants, and by quinine and ketoconazole a model system to predict drug interactions in vivo. J Pharmacol. Exp Ther 268, 1278–1283.Google Scholar
  146. Warner, M., Stromstedt, M., Wyss, A., and Gustafsson, J-A. (1993) Regulation of cytochrome P450 in the central nervous system J Steroid Bwchem Mol Biol 47, 191–194Google Scholar
  147. Waterman, M. R., Jenkins, C. M., and Pikuleva, I. (1995) Genetically engineered bacterial cells and applications. Toxicol. Lett 82183, 807–813Google Scholar
  148. Witte, D T, Ensing, K, Franke, J P, and Dezeeuw, R A (1993) Development and registration of chiral drugs Pharm World Sei 15, 10–16.Google Scholar
  149. Wrighton, S. A and Stevens, J C (1992) The human hepatic cytochromes P450 involved in drug metabolism Critical Reviews in Toxicology 22, 1–21PubMedGoogle Scholar
  150. Wu, D, Otton, S. V, Kalow, W., and Sellers, E. M (1995) Effects of route of administration on dextromethorphan pharmacokinetics and behavioural response in the rat J Pharmacol Exp Ther 274, 1431–1437PubMedGoogle Scholar
  151. Yasui, N, Koichi, O, Kaneko, S, et al (1996) A kinetic and dynamic study of oral alprazolam with and without erythromycin in humans In vivo evidence for the involvement of CYP3A4 in alprazolam metabolism Clin Pharmacol Ther 59, 514–519PubMedGoogle Scholar
  152. Yasumon, T, Qing-Hua, L, Yamazoe, Y, et al (1994) Lack of low Km diaz epam N-demethylase in livers of poor metabohzers for S-mephenytoin 4-hydroxylation Pharmacogenetics 4, 323–331Google Scholar
  153. Young, R C (1991) Hydroxylated metabolites of antidepressants Psychopharmacol Bull 27, 521–532PubMedGoogle Scholar
  154. Young, D, Midha, K K, Fossler, M J., Hawes, E M, Hubbard, J W, McKay, G, and Korchinski, E D. (1993) Effect of qumidine on the interconversion kinetics between halopendol and reduced halopendol in humans implica tions for the involvement of cytochrome P450IID6 Eur J Clin Pharmacol 44, 433–438.PubMedGoogle Scholar
  155. Zum Brunnen, T L and Jann, M W (1998) Drug interactions with antipsy chotic agents CNS Drugs 9, 381–401Google Scholar

Copyright information

© Humana Press Inc 1999

Authors and Affiliations

  • Ronald T. Coutts
    • 1
  • jian Fang
    • 2
  • Michel Bourin
    • 3
  • Glen B. Baker
    • 4
  1. 1.Neurochemzcal Research Unit, Department of PsychiatryWalker Mackenzie Centre, University of AlbertaEdmonton, AlbertaCanada
  2. 2.College of Pharmacy and NutritionUniverstty of SaskatchewanSaskatoon, SaskatchewanCanada
  3. 3.Laboratozre de Pharmcologie, Faculté de Médecine, Université de Nantes, Nantes, France, and Neurochemical Research Unit, Department of Psychiatry, Walker Mackenzze CentreUniversity of AlbertaEdmonton, AlbertaCanada
  4. 4.Neurochemical Research Unit, Department of Psychiatry, Walker Mackenzie CentreUniversity of AlbertaEdmonton, AlbertaCanada

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